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Diversity of Long-Lived Intermediates along the Binding Pathway of Imatinib to Abl Kinase Revealed by MD Simulations. | LitMetric

Diversity of Long-Lived Intermediates along the Binding Pathway of Imatinib to Abl Kinase Revealed by MD Simulations.

J Chem Theory Comput

Department of Biochemistry and Molecular Biology, The University of Chicago, Chicago, Illinois 60637, United States.

Published: December 2020

Imatinib, a drug used for the treatment of chronic myeloid leukemia and other cancers, works by blocking the catalytic site of pathological constitutively active Abl kinase. While the binding pose is known from X-ray crystallography, the different steps leading to the formation of the complex are not well understood. The results from extensive molecular dynamics simulations show that imatinib can primarily exit the known crystallographic binding pose through the cleft of the binding site or by sliding under the αC helix. Once displaced from the crystallographic binding pose, imatinib becomes trapped in intermediate states. These intermediates are characterized by a high diversity of ligand orientations and conformations, and relaxation timescales within this region may exceed 3-4 ms. Analysis indicates that the metastable intermediate states should be spectroscopically indistinguishable from the crystallographic binding pose, in agreement with tryptophan stopped-flow fluorescence experiments.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8288498PMC
http://dx.doi.org/10.1021/acs.jctc.0c00739DOI Listing

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